John Svaren, PhD

Position title: Professor, Comparative Biosciences

PhD, Vanderbilt University
Director, IDD Models Core

Contact Information

Waisman Center
Room 659
1500 Highland Avenue
Madison, WI 53705
608-263-4246
jpsvaren@wisc.edu
Lab Website: Svaren Lab Home Page
School of Veterinary Medicine

Research Statement

Our laboratory is devoted to research on transcriptional and epigenomic regulation of myelination and pathogenesis/treatment of peripheral neuropathies. The myelin sheath that insulates peripheral nerve fibers is critical for efficient conduction of nerve signals through motor and sensory nerves. Myelin is produced by Schwann cells in a developmental process that is triggered by their association with developing axons.

I have a long standing interest in the interplay of chromatin structure and gene regulation, and we were the first to develop chromatin immunoprecipitation analysis to identify regulatory elements in myelin-associated genes in vivo. These techniques have been combined with epigenomics tools (ChIP-Seq) to characterize genetic/epigenetic mechanisms of myelin formation and how these mechanisms are altered in disorders affecting myelination. We have investigated the role of epigenomic changes in the dynamic reprogramming of Schwann cells after nerve injury, as Schwann cells are a major determinant in the ultimate regeneration and remyelination of axons after nerve injury. Our studies have identified the polycomb pathway as an important regulator of many nerve injury genes, and these efforts were also the first to identify injury-regulated enhancers in peripheral nerve.

Genetic conditions affecting myelin formation and maintenance by Schwann cells are some of the most common forms of inherited disease in the nervous system, including Charcot-Marie-Tooth disease (CMT). Our studies also include translational projects as we have been mapped regulatory elements in the human PMP22 gene, which is duplicated in one of the most common forms of the heritable peripheral neuropathy known as Charcot-Marie-Tooth disease. Our studies have identified novel therapeutic strategies to treat Charcot-Marie-Tooth disease, and we have implemented discovery approaches for novel biomarker assessments that can be used in clinical trials for CMT1A and other major forms of CMT. As part of these efforts, I am currently a board member of the Charcot-Marie-Tooth Association, and serve as chair of its scientific advisory board.

Selected Publications

Pubmed

Pipis, M., Won, S., Poh, R., Efthymiou, S., Polke, J. M., Skorupinska, M., Blake, J., Rossor, A. M., Moran, J. J., Munot, P., Muntoni, F., Laura, M., Svaren, J., & Reilly, M. M. (2023). Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1. Brain : a journal of neurology, awad203. Advance online publication. https://doi.org/10.1093/brain/awad203
Duong, P., Ramesh, R., Schneider, A., Won, S., Cooper, A. J., & Svaren, J. (2023). Modulation of Schwann cell homeostasis by the BAP1 deubiquitinase. Glia, 71(6), 1466–1480. https://doi.org/10.1002/glia.24351
Ramesh, R., Manurung, Y., Ma, K. H., Blakely, T., Jr, Won, S., Moreno-Ramos, O. A., Wyatt, E., Awatramani, R., & Svaren, J. (2022).JUN regulation of injury-induced enhancers in Schwann cells. The Journal of Neuroscience, 42(34), 6506–6517. https://doi.org/10.1523/JNEUROSCI.2533-21.2022
Contreras, A., Wiesner, D. L., Kingstad-Bakke, B., Lee, W., Svaren, J. P., Klein, B. S., & Suresh, M. (2022). BACH2 in TRegs limits the number of adipose tissue regulatory T cells and restrains type 2 immunity to fungal allergens. Journal of Immunology Research, 2022, 6789055. https://doi.org/10.1155/2022/6789055
Veneri, F. A., Prada, V., Mastrangelo, R., Ferri, C., Nobbio, L., Passalacqua, M., Milanesi, M., Bianchi, F., Del Carro, U., Vallat, J. M., Duong, P., Svaren, J., Schenone, A., Grandis, M., & D’Antonio, M. (2022). A novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism. Human Molecular Genetics, 31(24), 4255–4274. https://doi.org/10.1093/hmg/ddac170
Park, H. J., Tsai, E., Huang, D., Weaver, M., Frick, L., Alcantara, A., Moran, J. J., Patzig, J., Melendez-Vasquez, C. V., Crabtree, G. R., Feltri, M. L., Svaren, J., & Casaccia, P. (2022). ACTL6a coordinates axonal caliber recognition and myelination in the peripheral nerve. iScience, 25(4), 104132. https://doi.org/10.1016/j.isci.2022.104132
Wang, H., Davison, M., Wang, K., Xia, T. H., Call, K. M., Luo, J., Wu, X., Zuccarino, R., Bacha, A., Bai, Y., Gutmann, L., Feely, S., Grider, T., Rossor, A. M., Reilly, M. M., Shy, M. E., & Svaren, J. (2021). MicroRNAs as Biomarkers of Charcot-Marie-Tooth Disease Type 1A. Neurology, 97(5), e489–e500. https://doi.org/10.1212/WNL.0000000000012266
Duong, P., Ma, K. H., Ramesh, R., Moran, J. J., Won, S., & Svaren, J. (2021). H3K27 demethylases are dispensable for activation of Polycomb-regulated injury response genes in peripheral nerve. The Journal of biological chemistry, 297(1), 100852. https://doi.org/10.1016/j.jbc.2021.100852
Grosz, B. R., Svaren, J., Perez-Siles, G., Nicholson, G. A., & Kennerson, M. L. (2021). Revisiting the pathogenic mechanism of the GJB1 5′ UTR c.-103C > T mutation causing CMTX1. Neurogenetics, 22(3), 149–160. https://doi.org/10.1007/s10048-021-00650-9
Martinez, N. J., Braisted, J. C., Dranchak, P. K., Moran, J. J., Larson, H., Queme, B., Pak, E., Dutra, A., Rai, G., Cheng, K. C., Svaren, J., & Inglese, J. (2021). Genome-Edited Coincidence and PMP22-HiBiT Fusion Reporter Cell Lines Enable an Artifact-Suppressive Quantitative High-Throughput Screening Strategy for PMP22 Gene-Dosage Disorder Drug Discovery. ACS pharmacology & translational science, 4(4), 1422–1436. https://doi.org/10.1021/acsptsci.1c00110
Lupo, V., Won, S., Frasquet, M., Schnitzler, M. S., Komath, S. S., Pascual-Pascual, S. I., Espinós, C., Svaren, J., & Sevilla, T. (2020). Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex. European journal of neurology, 27(12), 2662–2667. https://doi.org/10.1111/ene.14512
Pantera, H., Hu, B., Moiseev, D., Dunham, C., Rashid, J., Moran, J. J., Krentz, K., Rubinstein, C. D., Won, S., Li, J., & Svaren, J. (2020). Pmp22 super-enhancer deletion causes tomacula formation and conduction block in peripheral nerves. Human molecular genetics, 29(10), 1689–1699. https://doi.org/10.1093/hmg/ddaa082
Wang H, Davison M, Wang K, Xia TH, Kramer M, Call K, Luo J, Wu X, Zuccarino R, Bacon C, Bai Y, Moran JJ, Gutmann L, Feely SME, Grider T, Rossor AM, Reilly MM, Svaren J, Shy ME. (2020). Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A. Annals of Clinical and Translational Neurology, 7(1):69-82. doi: 10.1002/acn3.50965.
Pantera H, Shy ME, Svaren J. (2020). Regulating PMP22 expression as a dosage sensitive neuropathy gene. Brain Research, 1;1726:146491. doi: 10.1016/j.brainres.2019.146491.
Svaren J, Moran JJ, Wu X, Zuccarino R, Bacon C, Bai Y, Ramesh R, Gutmann L, Anderson DM, Pavelec D, Shy ME. (2019). Schwann Cell Transcript Biomarkers for Hereditary Neuropathy Skin Biopsies. Annals of Neurology, 85(6):887-898. doi: 10.1002/ana.25480.
Belin S, Ornaghi F, Shackleford G, Wang J, Scapin C, Lopez-Anido C, Silvestri N, Robertson N, Williamson C, Ishii A, Taveggia C, Svaren J, Bansal R, Schwab MH, Nave K, Fratta P, D’Antonio M, Poitelon Y, Feltri ML, Wrabetz L. (2019). Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy. Human Molecular Genetics, 28(8):1260-1273. doi: 10.1093/hmg/ddy420.
Tao F, Beecham GW, Rebelo AP, Blanton SH, Moran JJ, Lopez-Anido C, Svaren J, Abreu L, Rizzo D, Kirk CA, Wu X, Feely S, Verhamme C, Saporta MA, Herrmann DN, Day JW, Sumner CJ, Lloyd TE, Li J, Yum SW, Taroni F, Baas F, Choi BO, Pareyson D, Scherer SS, Reilly MM, Shy ME, Züchner S; Inherited Neuropathy Consortium. (2019). Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study. Journal of Neuromuscular Diseases, 6(2):201-211. doi: 10.3233/JND-190377.
Tao F, Beecham GW, Rebelo AP, Blanton SH, Moran JJ, Lopez-Anido C, Svaren J, Morrow JM, Abreu L, Rizzo D, Kirk CA, Wu X, Feely S, Verhamme C, Saporta MA, Herrmann DN, Day JW, Sumner CJ, Lloyd TE, Li J, Yum SW, Taroni F, Baas F, Choi BO, Pareyson D, Scherer SS, Reilly MM, Shy ME, Züchner S; Inherited Neuropathy Consortium. (2019). Variation in SIPA1L2 is Correlated with Phenotype Modification in CMT Type 1A. Annals of Neurology, 85(3):316-330. doi: 10.1002/ana.25426
Ma KH, Svaren J. (2018). Epigenetic Control of Schwann Cells. Neuroscientist, 24(6):627-638. doi: 10.1177/1073858417751112.
Zhao HT, Damle S, Ikeda-Lee K, Kuntz S, Li J, Mohan A, Kim A, Hung G, Scheideler MA, Scherer SS, Svaren J, Swayze EE, Kordasiewicz HB. (2018). PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models. Journal of Clinical Investigation. 128(1):359-368. doi: 10.1172/JCI96499.
Duncan ID, Bugiani M, Radcliff AB, Moran JJ, Lopez-Anido C, Duong P, August BK, Wolf NI, van der Knaap MS, Svaren J. (2017) A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination. Annals of Neurology. 81(5):690-702. doi: 10.1002/ana.24930.
Rodríguez-Molina JF, Lopez-Anido C, Ma KH, Zhang C, Olson T, Muth KN, Weider M, Svaren J. (2017) Dual specificity phosphatase 15 regulates Erk activation in Schwann cells. Journal of Neurochemistry. 140(3):368-382. doi: 10.1111/jnc.13911.
Gopinath C, Law WD, Rodríguez-Molina JF, Prasad AB, Song L, Crawford GE, Mullikin JC, Svaren J, Antonellis A. (2016) Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation. BMC Genomics. 17(1):887.
Ma KH, Hung HA, Svaren J. (2016) Epigenomic Regulation of Schwann Cell Reprogramming in Peripheral Nerve Injury. Journal of Neuroscience. 36(35):9135-47. doi: 10.1523/JNEUROSCI.1370-16.2016.
Fogarty EA, Brewer MH, Rodriguez-Molina JF, Law WD, Ma KH, Steinberg NM, Svaren J, Antonellis A. (2016) SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2. Human Molecular Genetics. 15;25(18):3925-3936. doi: 10.1093/hmg/ddw233.
Poitelon Y, Lopez-Anido C, Catignas K, Berti C, Palmisano M, Williamson C, Ameroso D, Abiko K, Hwang Y, Gregorieff A, Wrana JL, Asmani M, Zhao R, Sim FJ, Wrabetz L, Svaren J, Feltri ML. (2016) YAP and TAZ control peripheral myelination and the expression of laminin receptors in Schwann cells. Nature Neuroscience. 19(7):879-87. doi: 10.1038/nn.4316.
Lopez-Anido C, Poitelon Y, Gopinath C, Moran JJ, Ma KH, Law WD, Antonellis A, Feltri ML, Svaren J. (2016) Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development. Human Molecular Genetics. 15;25(14):3055-3069.
Lopez-Anido C, Sun G, Koenning M, Srinivasan R, Hung HA, Emery B, Keles S, Svaren J. (2015) Differential Sox10 genomic occupancy in myelinating glia. Glia, 63:1897–1914. doi: 10.1002/glia.22855.
Romens SE, McDonald J, Svaren J, Pollak SD. (2015) Associations Between Early Life Stress and Gene Methylation in Children. Child Development. 86(1):303-9. doi: 10.1111/cdev.12270.
Ma KH, Hung HA, Srinivasan R, Xie H, Orkin SH, Svaren J. (2015) Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2. Journal of Neuroscience, 35(22):8640-52. doi: 10.1523/JNEUROSCI.2257-14.2015.
Hung HA, Sun G, Keles S, Svaren J. (2015) Dynamic regulation of Schwann cell enhancers after peripheral nerve injury. Journal of Biological Chemistry, 13;290(11):6937-50. doi: 10.1074/jbc.M114.622878.
Inglese J, Dranchak P, Moran JJ, Jang SW, Srinivasan R, Santiago Y, Zhang L, Guha R, Martinez N, MacArthur R, Cost GJ, Svaren J. (2014) Genome Editing-Enabled HTS Assays Expand Drug Target Pathways for Charcot-Marie-Tooth Disease. ACS Chemical Biology. 21;9(11):2594-602. doi: 10.1021/cb5005492.
Sun G, Srinivasan R, Lopez-Anido C, Hung HA, Svaren J, Keleş S. (2014) In Silico Pooling of ChIP-seq Control Experiments. PLoS One. 9(11):e109691.
Brewer MH, Ma KH, Beecham GW, Gopinath C, Baas F, Choi BO, Reilly MM, Shy ME, Züchner S, Svaren J, Antonellis A. (2014) Haplotype-specific modulation of a SOX10/CREB response element at the Charcot-Marie-Tooth disease type 4C locus SH3TC2. Human Molecular Genetics. 23(19):5171-87.
Svaren J. (2014) MicroRNA and transcriptional crosstalk in myelinating glia. Neurochemistry International. 77:50-7.
Jones EA, Brewer MH, Srinivasan R, Krueger C, Sun G, Charney KN, Keles S, Antonellis A, Svaren J. (2012) Distal enhancers upstream of the Charcot-Marie-Tooth type 1A disease gene PMP22. Human Molecular Genetics. Apr 1;21(7):1581-91.
Oliver SS, Musselman CA, Srinivasan R, Svaren JP, Kutateladze TG, Denu JM. (2012) Multivalent recognition of histone tails by the PHD fingers of CHD5. Biochemistry. 51(33):6534-44.
Hodonsky CJ, Kleinbrink EL, Charney KN, Prasad M, Bessling SL, Jones EA, Srinivasan R, Svaren J, McCallion AS, Antonellis A. (2012) SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1) locus in Schwann cells via an alternative promoter. Molecular and Cellular Biology. Feb;49(2):85-96.
Gokey NG, Srinivasan R, Lopez-Anido C, Krueger C, Svaren J. (2012) Developmental regulation of microRNA expression in Schwann cells. Molecular and Cellular Biology. Jan;32(2):558-68.
Srinivasan R, Sun G, Keles S, Jones EA, Jang SW, Krueger C, Moran JJ, Svaren J. (2012) Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve. Nucleic Acids Research. 40(14):6449-60.
Hung H, Kohnken R, Svaren J. (2012) The nucleosome remodeling and deacetylase chromatin remodeling (NuRD) complex is required for peripheral nerve myelination. Journal of Neuroscience. Feb 1;32(5):1517-27.
Gokey NG, Lopez-Anido C, Gillian-Daniel AL, Svaren J. (2011) Early growth response 1 (Egr1) regulates cholesterol biosynthetic gene expression. Journal of Biological Chemistry. Aug 26;286(34):29501-10.